Clinical/surgical considerations.

While there are a diverse number of indications for the potential use of cell and gene therapies in people, many of the medical conditions being treated need to consider some general clinical and surgical issues, not only in designing clinical trials, but also in the eventual application of the therapy if shown to be successful. Such issues include the precision of the diagnosis and stage of disease, the presence of significant comorbidity, as well as the challenges that may be encountered in trial designs involving the neurosurgical delivery of these advanced interventions. This chapter discusses details of these issues that have arisen particularly in the field of Parkinson disease and other forms of neurodegeneration, although the general principles and considerations discussed may be equally relevant to other neurologic and nonneurologic conditions.

Screening embryos for polygenic disease risk: a review of epidemiological, clinical, and ethical considerations.

BACKGROUND: The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation genetic testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural variants, and aneuploidy. Recent advances have made genome-wide genotyping of IVF embryos feasible and affordable, raising the possibility of screening embryos for their risk of polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia. Despite a heated debate around this new technology, called polygenic embryo screening (PES; also PGT-P), it is already available to IVF patients in some countries. Several articles have studied epidemiological, clinical, and ethical perspectives on PES; however, a comprehensive, principled review of this emerging field is missing. OBJECTIVE AND RATIONALE: This review has four main goals. First, given the interdisciplinary nature of PES studies, we aim to provide a self-contained educational background about PES to reproductive specialists interested in the subject. Second, we provide a comprehensive and critical review of arguments for and against the introduction of PES, crystallizing and prioritizing the key issues. We also cover the attitudes of IVF patients, clinicians, and the public towards PES. Third, we distinguish between possible future groups of PES patients, highlighting the benefits and harms pertaining to each group. Finally, our review, which is supported by ESHRE, is intended to aid healthcare professionals and policymakers in decision-making regarding whether to introduce PES in the clinic, and if so, how, and to whom. SEARCH METHODS: We searched for PubMed-indexed articles published between 1/1/2003 and 1/3/2024 using the terms 'polygenic embryo screening', 'polygenic preimplantation', and 'PGT-P'. We limited the review to primary research papers in English whose main focus was PES for medical conditions. We also included papers that did not appear in the search but were deemed relevant. OUTCOMES: The main theoretical benefit of PES is a reduction in lifetime polygenic disease risk for children born after screening. The magnitude of the risk reduction has been predicted based on statistical modelling, simulations, and sibling pair analyses. Results based on all methods suggest that under the best-case scenario, large relative risk reductions are possible for one or more diseases. However, as these models abstract several practical limitations, the realized benefits may be smaller, particularly due to a limited number of embryos and unclear future accuracy of the risk estimates. PES may negatively impact patients and their future children, as well as society. The main personal harms are an unindicated IVF treatment, a possible reduction in IVF success rates, and patient confusion, incomplete counselling, and choice overload. The main possible societal harms include discarded embryos, an increasing demand for 'designer babies', overemphasis of the genetic determinants of disease, unequal access, and lower utility in people of non-European ancestries. Benefits and harms will vary across the main potential patient groups, comprising patients already requiring IVF, fertile people with a history of a severe polygenic disease, and fertile healthy people. In the United States, the attitudes of IVF patients and the public towards PES seem positive, while healthcare professionals are cautious, sceptical about clinical utility, and concerned about patient counselling. WIDER IMPLICATIONS: The theoretical potential of PES to reduce risk across multiple polygenic diseases requires further research into its benefits and harms. Given the large number of practical limitations and possible harms, particularly unnecessary IVF treatments and discarded viable embryos, PES should be offered only within a research context before further clarity is achieved regarding its balance of benefits and harms. The gap in attitudes between healthcare professionals and the public needs to be narrowed by expanding public and patient education and providing resources for informative and unbiased genetic counselling.

Switching to Tirzepatide 5 mg From Glucagon-Like Peptide-1 Receptor Agonists: Clinical Expectations in the First 12 Weeks of Treatment.

OBJECTIVE: This prospective study aimed to describe the clinical course in terms of glycemic outcomes, body weight, and adverse events during the first 12 weeks following a switch from glucagon-like peptide-1 receptor agonists (GLP-1 RAs) directly to tirzepatide 5 mg. METHODS: Participants were ≥18 years with type 2 diabetes (T2D), glycated hemoglobin (HbA1c) ≥6.5% to ≤9.0%, body mass index ≥25 kg/m2 and were on a stable treatment dose of GLP-1 RAs (liraglutide every day [1.2, 1.8 mg], semaglutide once-weekly [0.5, 1.0, 2.0 mg], or dulaglutide once-weekly [0.75, 1.5, 3.0, and 4.5 mg]) for ≥3 months at baseline. The primary end point was HbA1c change from baseline at week 12. Secondary end points included change from baseline in fasting serum glucose, body weight, and glucose assessed by continuous glucose monitoring. Safety was also assessed. RESULTS: Participants were 58.3 years on average, with baseline HbA1c 7.39%, body mass index 35.18 kg/m2, T2D duration around 12.4 years, and included 55% females. Semaglutide (55%) and dulaglutide (42%) were the most commonly used GLP-1 RAs at baseline with semaglutide 1.0 mg and dulaglutide 1.5 mg being the most common treatment doses. At week 12, mean HbA1c changed from baseline by -0.43%, fasting serum glucose by -7.83 mg/dL, and body weight by -2.15 kg (all P < .01). Glycemic outcomes and body weight improved in participants in all baseline GLP-1 RA subgroups. Twenty participants (13.2%) developed gastrointestinal events. Three (2%) participants discontinued tirzepatide due to adverse events. There were no severe hypoglycemic events or deaths. CONCLUSION: In this prospective study, when people with T2D on stable GLP-1 RA treatment were switched directly to tirzepatide 5 mg, they experienced improved glycemic outcomes and additional weight reduction with an acceptable risk of adverse gastrointestinal events over 12 weeks.

Intermittent catheterisation.

When an individual has voiding difficulties, the person may require a urinary catheter. Enabling the person to choose an appropriate method of catheterisation and supporting them can have an enormous impact on the individual's health and wellbeing. Indwelling urethral catheters are suitable for some people but for others they can affect a person's lifestyle and lead to depression. Intermittent catheterisation can work well for some people. Intermittent self-catheterisation has been used to manage urinary retention for over 3500 years. It remains the 'gold standard' in terms of bladder drainage, but it is under-used and indwelling catheters remain more common. This article examines the history of intermittent catheterisation, indications for self-catheterisation and how to support people to use self-catheterisation.

Síndrome de Sjögren y endodoncia, consideraciones a propósito de un caso / Sjögren's syndrome and endodontics, clinical case and considerations

El síndrome de Sjögren (SS) es una enfermedad autoinmune que afecta a las glándulas salivales y lagrimales. Se expone el caso clínico de una paciente de 67 años de género femenino que consulta por dolor en múltiples dientes; relata sensación de boca seca (xerostomía) y sequedad ocular (xeroftalmia). Al examen intraoral, se observan múltiples caries en superficies atípicas, mucosas secas, saliva espumosa y notoria depapilación lingual. Se sospecha de SS, derivando a medicina interna y confirmándose el diagnóstico. En paralelo, se inicia el tratamiento odontológico, realizando adaptaciones en los procedimientos para aliviar la sintomatología del SS, especialmente durante tratamientos endodónticos.

Sjögren's syndrome (SS) is an autoimmune disease that affects the salivary and lacrimal glands. The clinical case of a 67-year-old female patient who consulted for pain in multiple teeth is exposed. Additionally, she reports a sensation of dry mouth (xerostomia) and dry eyes (xerophthalmia). During the intraoral examination, the following findings are noticed: multiple cavities on atypical surfaces, dry mucous membranes, foamy saliva, and atrophic glossitis. SS is suspected, referring to internal medicine and confirming the diagnosis. In parallel, dental treatment is initiated, making adaptations in the procedures to alleviate the symptoms of SS, especially during endodontic treatments.

The Regulation of Cell Therapy and Gene Therapy Products in Switzerland.

This chapter describes the regulation of cell and gene therapy products (CGTPs) in Switzerland and its legal basis. The Swiss Agency for Therapeutic Products, Swissmedic, is the lead Regulatory Authority and its ATMP Division is responsible for the regulation of these products at the level of clinical trials and marketing authorization. CGTPs are regulated similarly to medicinal products. The legal basis is set by the Therapeutic Product Act, the Transplantation Act, the Human Research Act, and associated ordinances. The ATMP Division is involved in processes such as scientific advice meetings, presubmission advice meetings, pharmacovigilance, market surveillance, import/export approvals, manufacturing license approval, and inspections. In Switzerland, guidance documents relevant for cell and gene therapy provided by PIC/S, OECD, ICH, Ph.Eur., EMA, or FDA are considered. In order to harmonize requirements for CGTPs, the ATMP Division is in constant exchange of information with foreign Regulatory Authorities and part of working groups of ICH, IPRP, and Ph.Eur. As CGTPs are biologically and technically complex, a risk-based approach is applied on a case-by-case basis for the evaluation of clinical trial and marketing applications. A substantial part of this chapter will provide requirements with respect to the manufacturing and quality, nonclinical and clinical evaluation of CGTPs. Furthermore, information will be provided regarding the use of real-world evidence in evaluation of clinical long-term efficacy and safety in case of rare diseases where the numbers of patients are too small for statistically meaningful analysis during clinical trials. Finally, the chapter will provide information on a health technology assessment (HTA) program that was launched in 2015 in Switzerland by the federal authorities.

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Helicobacter pylori (H. pylori), for a long time, has generally been considered an extracellular bacterium. However, recent findings have shown that H. pylori can gain entry into host cells, evade attacks from the host immune system and the killing ability of medication, form stable intracellular ecological niche, and achieve re-release into the extracellular environment, thus causing recurrent infections. H. pylori intracellular infection causes cellular signaling and metabolic alterations, which may be closely associated with the pathogenesis and progression of tumors, thereby presenting new challenges for clinical eradicative treatment of H. pylori. Herein, examining this issue from a clinical perspective, we reviewed reported findings on the mechanisms of how H. pylori achieved intracellular infection, including the breaching of the host cell biological barrier, immune evasion, and resistance to autophagy. In addition, we discussed our reflections and the prospects of important questions concerning H. pylori, including the clinical prevention and control strategy, intracellular derivation, and the damage to host cells.

Functional assessment of glaucoma: Uncovering progression.

Clinicians who manage glaucoma patients carefully monitor the visual field to determine if treatments are effective or interventions are needed. Visual field tests may reflect disease progression or variability among examinations. We describe the approaches and perimetric tests used to evaluate glaucomatous visual field progression and factors that are important for identifying progression. These include stimulus size, which area of the visual field to assess (central versus peripheral), and the testing frequency, evaluating which is important to detect change early while minimizing patient testing burden. We also review the different statistical methods developed to identify change. These include trend- and event-based analyses, parametric and nonparametric tests, population-based versus individualized approaches, as well as pointwise and global analyses. We hope this information will prove useful and important to enhance the management of glaucoma patients. Overall, analysis procedures based on series of at least 5 to 6 examinations that require confirmation and persistence of changes, that are guided by the pattern and shape of the glaucomatous visual field deficits, and that are consistent with structural defects provide the best clinical performance.

Biomaterials and Scaffold Design Strategies for Regenerative Endodontic Therapy.

Challenges with traditional endodontic treatment for immature permanent teeth exhibiting pulp necrosis have prompted interest in tissue engineering approaches to regenerate the pulp-dentin complex and allow root development to continue. These procedures are known as regenerative endodontic therapies. A fundamental component of the regenerative endodontic process is the presence of a scaffold for stem cells from the apical papilla to adhere to, multiply and differentiate. The aim of this review is to provide an overview of the biomaterial scaffolds that have been investigated to support stem cells from the apical papilla in regenerative endodontic therapy and to identify potential biomaterials for future research. An electronic search was conducted using Pubmed and Novanet databases for published studies on biomaterial scaffolds for regenerative endodontic therapies, as well as promising biomaterial candidates for future research. Using keywords "regenerative endodontics," "scaffold," "stem cells" and "apical papilla," 203 articles were identified after duplicate articles were removed. A second search using "dental pulp stem cells" instead of "apical papilla" yielded 244 articles. Inclusion criteria included the use of stem cells from the apical papilla or dental pulp stem cells in combination with a biomaterial scaffold; articles using other dental stem cells or no scaffolds were excluded. The investigated scaffolds were organized in host-derived, naturally-derived and synthetic material categories. It was found that the biomaterial scaffolds investigated to date possess both desirable characteristics and issues that limit their clinical applications. Future research investigating the scaffolds presented in this article may, ultimately, point to a protocol for a consistent, clinically-successful regenerative endodontic therapy.

Qualitative Study on the Impact of Child Sexual Abuse: Perspectives of Children, Caregivers, and Professionals in Indian Context.

With an alarming increase in reported cases of Child Sexual Abuse (CSA) in India, the present study was conceived in an attempt to unearth the impact of CSA from the perspective of children, their caregivers, and the professionals dealing with them using qualitative research methodology. The secondary objective of the study was to discuss the clinical implications of the obtained findings for conducting culturally sensitive psychological assessment and intervention for CSA in India. Thus, in-depth interviews with 11 children and 7 Focused Group Discussions (FGDs) with 21 caregivers and 27 professionals were conducted. A total of 59 sample participants were recruited, and a thematic analysis was done. Six broad themes were identified from 223 generated codes-impact on behavioral, emotional, cognitive functioning and academics, psychopathology, biological, and social functioning. Four essential recommendations were concluded from the study, i.e., multidimensional impact assessment as a mandatory clinical practice, developing and utilizing culturally sensitive assessment & intervention protocols, incorporation of family-focused approach and multidisciplinary treatment team approach to ensure the holistic well-being of each chilsd in India.

Revascularization-associated Intracanal Calcification: A Case Report with an 8-year Review.

Revascularization-associated intracanal calcification (RAIC) is a common finding in immature teeth managed with regenerative endodontic treatment (RET). The aim of this report was to illustrate a case in which 2 mandibular premolar teeth developed complete canal obliteration and have been reviewed for 8 years. The 3 primary outcome goals as defined by the American Association of Endodontists after RET are resolution of signs and symptoms of pulp necrosis, further root maturation, and achievement of responses to pulp vitality testing. The teeth had been included in an earlier quantitative study in which an increase in root canal width of 72.1% and 39.6% and an increase in root length of 1.7% and 0% were reported for teeth #20 and #29, respectively. Qualitative assessments over the 8-year review period showed no pathosis and a response to electric pulp testing at the final review. A quantitative assessment at the 8-year review showed an increase of 100% for canal width because complete calcification had occurred and no substantive change in root length (-0.17% and 0.68% for teeth #20 and #29, respectively). In this report, complete RAIC occurred in both teeth over time. RAIC has the potential to complicate future endodontic or prosthodontic treatment if necessary. Therefore, it is recommended that the American Association of Endodontists clinical considerations for a regenerative endodontic procedure be updated to include the incidence of RAIC after RET.

Posttraumatic stress disorder and positive memories: Clinical considerations.

Encoding and retrieval difficulties, and avoidance of both traumatic and positive memories, are associated with posttraumatic stress disorder (PTSD) symptoms. However, most PTSD research and clinical work has solely examined the role of traumatic memories in the maintenance/resolution of PTSD symptoms. This review provides a comprehensive discussion of the literature on positive memories and PTSD. First, we review theories and evidence on the relations between trauma, PTSD, and memory processes (particularly positive memories). Next, we propose a conceptual model that integrates evidence from experimental and positive/memory-based intervention research and highlights hypothesized mechanisms underlying the potential effectiveness of targeting positive memories in PTSD interventions. Specifically, we discuss how targeting positive memories could (1) increase positive affect and reduce negative affect, (2) correct negative cognitions, (3) increase specificity of retrieving autobiographical memories, and (4) be effectively integrated/sequenced with and enhance the effects of trauma-focused interventions. Lastly, we suggest clinical research avenues for investigating the relations between positive memories and PTSD, to possibly alter the current PTSD intervention paradigm focused only on traumatic memories. Overall, our proposed model drawing from experimental and intervention research, and outlining potential effects of targeting positive memories to reduce PTSD severity, needs further empirical investigation.

Ultrasound-based Techniques as Alternative Treatments for Chronic Wounds: A Comprehensive Review of Clinical Applications.

Ultrasound (US) waves have been recently developed for the treatment of different chronic wounds with promising therapeutic outcomes. However, the clinical efficacy of these techniques is still not fully understood and standard guidelines on dose ranges and possible side effects should be determined. This paper aims to comprehensively review the recent advances in US techniques for chronic wound treatment, their therapeutic efficacies, and clinical considerations and challenges. The databases of PubMed (1985-2017), EMBASE (1985-2017), Web of Sciences (1985-2017), Cochrane central library (1990-2017), and Google Scholar (1980-2017) were searched using the set terms. The obtained results were screened for the title and abstract by two authors and the relevant papers were reviewed for further details. Preclinical and clinical studies have shown strong evidence on the therapeutic efficiency of US in chronic wounds. The main limitation on developing clinical standard protocols of US for treatment of wounds is the lack of definite dose-response for each wound. However, spatial average temporal average is the main parameter for defining US dosage in wound treatment. The range of 0.5 to 3 W/cm2 is a range of dose exerting significant therapeutic outcomes and minimum adverse effects. Low-frequency US waves can accelerate the healing speed of open wounds as well as deep-tissue injuries. In addition, US waves show promising therapeutic efficacy for chronic wounds. To develop clinical US protocol for each wound type, further in vitro and in vivo preclinical and clinical trials are needed to reach an exact dose-response for each wound type.

Requirements for Clinical Trials with Gene Therapy and Transplant Products in Switzerland.

This chapter aims to describe and summarize the regulation of gene and cell therapy products in Switzerland and its legal basis. Product types are briefly described, as are Swiss-specific terminologies such as the term "transplant product," which means products manufactured from cells, tissues, or even whole organs. Although some parts of this chapter may show a guideline character, they are not legally binding, but represent the current thinking of Swissmedic, the Swiss Agency for Therapeutic Products. As so far the experience with marketing approval of gene therapy and cell therapy products in Switzerland is limited, this chapter focuses on the regulation of clinical trials conducted with these products. Quality, nonclinical, and clinical aspects are summarized separately for gene therapy products and transplant products.

Regulations and guidelines governing stem cell based products: Clinical considerations.

The use of stem cells as medicines is a promising and upcoming area of research as they may be able to help the body to regenerate damaged or lost tissue in a host of diseases like Parkinson's, multiple sclerosis, heart disease, liver disease, spinal cord damage, cancer and many more. Translating basic stem cell research into routine therapies is a complex multi-step process which entails the challenge related to managing the expected therapeutic benefits with the potential risks while complying with the existing regulations and guidelines. While in the United States (US) and European Union (EU) regulations are in place, in India, we do not have a well-defined regulatory framework for "stem cell based products (SCBP)". There are several areas that need to be addressed as it is quite different from that of pharmaceuticals. These range from establishing batch consistency, product stability to product safety and efficacy through pre-clinical, clinical studies and marketing authorization. This review summarizes the existing regulations/guidelines in US, EU, India, and the associated challenges in developing SCBP with emphasis on clinical aspects.